Gonadal hormones

Binaya Tamang
UCMS-TH
 Introduction

• Cholesterol: produces or precursor of all classes of steroid hormones.

o Glucocorticoids ( e.g. cortisol)

o Mineralocorticoids( e.g. aldosterone)
o Sex hormones
• Androgens
• Estrogens
• Progestins

• Produced by
• small quantities by adrenal cortex ( zona reticularis).
• Testes, ovary and corpus luteum
 Relation betn adrenal androgen and gonads

• Adrenal androgens are weak.

• Are carried by binding proteins to peripheral tissue.

• sex hormone binding protein
• albumin.

• Converted into a stronger androgens testosterone estrogen

• Estrogen from androstenedione and testosterone by aromatization. Rxn

by aromatase ( CYP 19).
• testes,
• ovaries,
• placenta,
• adrenal cortex
 Secretion of steroid hormone from gonads

• From: testes & ovaries

• Aim: sexual differentiation & reproduction.

• ↑↑ GnRH: hypothalamus

• ↑↑ LH & FSH: anterior pituitary gland

• Binds to receptor ↑ cAMP

LH: A) Testes ↑ Testosterone

• B) Ovaries ↑ estrogen & progesterone ( corpus luteum)

• FSH: growth of ovarian follicles & stimulates testicular spermatogenesis

 Ovaries, female
Testes, male
Isolated
estrogen (1929).
Progesterone ( 1934)
testosterone ( 1935).
 ANDROGENS
 Androgens are C19 steroids capable of producing certain masculinizing
effects
o maintain the normal structure and function of genital tract
o secondary male sex characteristics,

 Natural androgens
 Testosterone ( its active form is dihydrotestosterone-DHT)
 Androstenedione
 Dehydroepiandrosterone (DHEA) and its sulfate ( DHEA-S)

 Testosterone is the main androgen secreted by Leydig cell increases

during puberty
 Women produce about 5-10% as much as man do.
 FUNCTIONS OF TESTOTERONE
• Growth of genitals
• Growth of beard, body hair
• Skin thickening Acne problems
• Increased muscle strength and mass
• Deepening of voice
• Growth of spermatogenic tissue in testicles, male fertility
• Increased libido
• Growth of jaw, brow, chin, nose, and remodeling of facial bone contours,
in conjunction with human growth hormone
• Completion of bone maturation and termination of growth.
• Protein synthesis anabolic ( use by gymer too)
• Positive N2 balance
• Increase erythropoietin
• Mental: More aggressive, active attitude.
 ESTROGENS
• The naturally occurring estrogens in humans are
a) β-Estradiol
b) Estrone
c) Estriol

• β-estradiol: The principal circulation and most active

• Estriol: late stage of pregnancy
• Estrone : urine of pregnant woman & placenta.

• Essential Features:
• Aromatic character of ring A (three double bonds)
• Absence of –CH3 group at C10
• All are C18
 ESTROGENS-function
• for the development and maintenance
• female sex organs and female secondary sex characteristics.

• In conjunction with progesterone (C21, corpus luteum, placenta &

adrenal gland)

• the regulation of menstrual cycle

• breast and uterine growth
• maintenance of pregnancy

• Also effect calcium homeostasis and have beneficial role in bone mass.
• decrease bone resorption
• Post menopausal osteoporosis.
 Other Actions of Estrogens and Progestins
 High circulating levels of estrogen can cause mild glucose intolerance.

 Estrogens increase the synthesis of many liver proteins, including:

• transferrin, Sex Hormone Binding Globulin, corticosteroid-binding
globulin, and proteins involved in blood clotting (Increases blood
coagulability).

 Estrogens lower serum cholesterol levels by stimulating the formation of

HDL and reducing LDL.
 PROGESTERONE (C21)

• Progesterone is the hormone of the corpus luteum, the structure which

develops in the ovary from the ruptured graafian follicle.

• It is also formed by the placenta, which secretes progesterone, during the

later part of pregnancy.

• Progesterone is also formed in the adrenal cortex

• an intermediate in the biogenesis of adrenocortical hormones and of
androgens
• MOA : It is similar to estrogen
 Biosynthesis
• All steroid hormones are formed from cholesterol via pregnenolone
• mitochondria
• Smooth endoplasmic reticulum.
FIRST,
• cholesterol into mitochondria  by stAR transport protein
• Inner mitochondria: cytochrome P450 side chain cleavage enzyme
(P450scc) or desmolase  cholesterol to pregnenolone.

• removal of the side chain give 21-carbon steroid

 1st : ANDROGEN SYNTHESIS

• produced in
• testes (Leydig cells),
• adrenal cortex,
• ovary and placenta.

• precursor:
• acetate
• Cholesterol

• General step
• Cholesterol pregnenolone ( inner mitochondria, rate limiting
step) carried to smooth ER  testerone.
 Two pathways
 five enzyme activities in 3 proteins

• 3β-hydroxysteroid dehydrogenase (3β- OHSD) and ∆5,4-isomerase:

single protein

• 17α-hydroxylase and 17,20-lyase: single protein

• 17β-hydroxysteroid dehydrogenase (17β-OHSD)

 Two pathways
• progesterone (or ∆ 4) pathway
• dehydroepiandrosterone (or ∆ 5) pathway

Lets explain the process after pregnenolone is formed.

∆ 5 pathway ∆ 4 pathway

hydroxylation
C17

single protein Single protein

side chain
is lost

Reduced at
C17
 In simple

Androstenedione: immediate precursor

•Active form: testosterone is converted

•To Dihydrotestosterone( DHT) in
 Androgen transport & metabolism
 Transport
Testosterone + DHT:
• 2-3% free
• bound with plasma protein
Protein:
• sex hormone binding protein (SHBG)
• Non specific albumin.
• For biological activity: Both free + disassociated from protein
 Metabolism
• Testosterone converts into
• Active metabolites:
• Estradiol ( aromatase)
• DHT ( 5 ⍺ reductase)
• Excretory metabolites ( > 90% in urine)
• 17 keto steroids: Androsterone+ etiocholanolone( 17β0H-SD)
• Polar metabolites: diols , triols and conjugates ( hydroxylases, conjugating
enzymes)
 Dihydrotestosterone (DHT)
• Is Formed From Testosterone in Peripheral Tissues.

• The most significant/potent form: Active form

• 400 μg of DHT / daily vs about 5 mg of testosterone

• About 50–100 μg of DHT : testes
• Remaining by peripheral conversion.
 Some knowledge of adrenal androgens

• The major androgen or androgen precursor produced by the adrenal

cortex is dehydroepiandrosterone (DHEA).

• DHEA is really a prohormone,  convert the weak DHEA into the

more potent androstenedione.

• Androstenedione reduces testosterone

• Small amounts of testosterone are produced in the adrenal by this

mechanism, but most of this conversion occurs in the testes.
 2nd Estrogen: Biosynthesis
• primary estrogen of ovary: β-Estradiol
• In pregnancy(from the placenta): estriol
 Site:
• In ovary by maturing graffian follicles ( major)
• Also adrenal cortex testes in small amount
• Late pregnancy: estriol is predominant
• Transport in plasma : SHBG and Albumin.

Steps:
• The general pathway in the early steps are the same as in androgen
biosynthesis
• Precursor: testosterone and androstenedione.
• C19C18 ( by removal of CH3 at C10 and aromatization)
 Metabolites of estrogen

• Estradiol and estrone are reversible.

• Estradiol

• Estrone
(2-hydroxylation ) (16⍺ hydroxylation)
Methoxy derivatives estriol

In liver

conjugation with glucuronic acid

urine
 Mechanism of action
Free testosterone enters the target cells

In the cytoplasm converted to ‘active’ DHT

hormone-receptor complex

binds to the ‘hormone-responsive element’ (HRE) on gene

induces the transcription

↑↑ respective proteins

• Similar for estrogen too: ER-⍺ and ER-β are its receptor
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